Transcriptional regulation of subtilisin-like proprotein convertase PACE4 by E2F: possible role of E2F-mediated upregulation of PACE4 in tumor progression.
Transcriptional regulation of subtilisin-like proprotein convertase PACE4 by E2F: possible role of E2F-mediated upregulation of PACE4 in tumor progression.
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DOI：
10.1016/j.gene.2007.07.028
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发表时间：
2007-11
期刊：
影响因子：
3.5
通讯作者：
K. Yuasa;K. Suzue;M. Nagahama;Y. Matsuda;A. Tsuji
中科院分区：
文献类型：
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作者：
K. Yuasa;K. Suzue;M. Nagahama;Y. Matsuda;A. Tsuji
PACE 4是枯草杆菌蛋白酶样前蛋白转化酶（SPC）家族的成员，在某些肿瘤细胞中高水平表达，并通过激活基质金属蛋白酶在转移进展中发挥作用。导致肿瘤细胞中PACE 4过表达的机制尚不清楚。在这项研究中，我们发现，E2 F1转录因子，这是牵连在癌的侵袭，上调表达的PACE 4。HT 1080（高度致瘤性和侵袭性）细胞表达的PACE 4和E2 F家族（E2 F1和E2 F2）转录物水平远高于IMR 90（正常成纤维细胞）细胞。其他SPC（弗林蛋白酶和PC6）的表达水平在这些细胞中保持不变。启动子分析表明，人PACE 4基因5′侧翼区的两个E2 F共有结合位点（−117/−110和−86/−79）作为正调控元件发挥功能。这些位点的突变废除了PACE 4启动子对E2 F1的响应以及电泳迁移率变化测定中E2 F1的结合。其他E2 F成员，E2 F2和E2 F3，也激活了PACE 4的表达，如E2 F1的情况。这些结果表明E2 F家族介导的通过PACE 4促进癌侵袭的新机制。
PACE4, a member of the subtilisin-like proprotein convertase (SPC) family, is expressed at high levels in certain tumor cells and plays a role in metastatic progression through activation of matrix metalloproteinases. The mechanism leading to overexpression of PACE4 in tumor cells remains unclear. In this study, we show that the E2F1 transcription factor, which is implicated in carcinoma invasiveness, upregulates the expression of PACE4. HT1080 (highly tumorigenic and invasive) cells expressed much higher levels of PACE4 and E2F family (E2F1 and E2F2) transcripts than IMR90 (normal fibroblast) cells. Expression levels of other SPCs (furin and PC6) remained unchanged in these cells. Promoter analysis indicated that two E2F consensus binding sites (−117/−110 and −86/−79) in the 5′-flanking region of the human PACE4 gene function as positive regulatory elements. Mutation of these sites abolished PACE4 promoter response to E2F1 as well as binding of E2F1 in electrophoretic mobility-shift assays. Other E2F members, E2F2 and E2F3, also activated PACE4 expression, as in the case of E2F1. These results indicate a novel mechanism for E2F family-mediated promotion of carcinoma invasiveness through PACE4.